- Email: [email protected]
Rheumatoid arthritis
Rheumatoid Lars Klareskog,
Johan
Rbnelid,
Alex Uppsala
arthritis Sveinn
Cudmundsson
and
Karlsson-Parra
University,
Uppsala,
Sweden
The immunopathogenesis of rheumatoid arthritis is discussed in two ways. First, we consider the major question of whether T cells are likely to drive the disease. Second - and assuming T cells to be important we discuss available data on the components of the trimolecular complex (major histocompatibility complex class II-antigen-T-cell receptor), which are possibly involved in the disease. Our two main points are that the most important questions concerning the pathogenesis of rheumatoid arthritis require answers from immunointervention in patients, and that animal experiments can be increasingly used in interpreting current experiments in humans.
Current
Opinion
in Immunology
Introduction Rheumatoid arthritis (RA) is a diseasethat is mainly deiined by clinical criteria, in which systematicpathogenetic studies have been hampered by doubts about the presence of common pathogenetic mechanismsand the relative lack of unique laboratory findings. The two major observationsthat have altered this situation, and have deiined the present direction of research, are the demon stration of a lInkage between certain major histocompatibillty complex (MIX) classII allelesand diseasesusceptibility [ 1,2], and elucidation of the cellular events within the inilammatory lesions, primarily in the joints, which has led to suggestionsthat local MHC classII-dependent T-cell activation is the primary driving force in development of disease[35]. This review will focus on two major issuesconcerning our understanding of RA. We will discusswhether T-celldriven immune reactions are essentialin RA and, assuming such T-cell reactions are important, the components of the trimolecular complex (MIX classIIantigen-T-cell receptor) that determine the specificity of the putative arthrltogenic T-cell reactivities. In our attempts to discuss both these issues,we must consider the fact that only immunological intervention in RA patients can determine conclusively whether an immunological event is a driving force in the disease,or merely representsan epiphenomenon.
1991, 3:912-916
Driving forces in arthritis: evidence and aganist MHC class II-dependent activation
Although a role for T-cell activation in the pathogenesisof RA is assumedin both analytical and therapeutic studies, this assumption is still controversial. Thus, it is essential to heed all data reported that challenge this fundamental point. Recently, Firestein and Zvaifler [6**] questioned the role of T cells on the basis of three observations. First, the relative lack of certain characteristicsof activation in synovial T cells: particularly the lack of proliferation and low production of cytokines by T cells, compared with high cytokine production by macrophages. Second, the lack of clear evidence for clonal expansion of T cellsin the joint. Third, the lack of dramatic effects of drugs such ascyclosporin A, which affect T-cell activation. These points must be seriously considered by workers such as ourselves who maintain that the T-cell hypothesis is the most viable. A failure to counter these proposals would imply the need to search for mechanisms,for example virus-dependent events, that may causetransformation and proliferation of synovial cells without stimuli from activated T cells [7]. The first point- the lack of synovial T-cell activation - has been studied experimentally by Zavaifler and Firestein’s groups. Evidence of a relatively low synovial production of T-cell cytokines such as interleukin (IL)-2
Abbreviations CRP-C-reactive protein; ESR-erythrocyte sedimentation rate; GM-CS~ranulocyte-macrophage colony-stimulating factor; IFN-interferon; MHC-major RA-rheumatoid arthritis; R&rheumatoid factor; TN&tumor necrosis
912
(EJ Current
Biology
for T-cell
Ltd ISSN
0952-7915
histocompatibility factor.
complex;
Rheumatoid
and interferon (IFNI-y and high production of cytokines such as tumor necrosis factor (TNF)-a and granulocytemarcophage colony-stimulating factor (GM-CSF), which are mainly produced by activated macrophages,hasbeen reported [@*I. There have also been reports of very limited T-cell proliferative activity within the joints [6-l, a feature compatible with the relatively low IL-2 receptor expression that is seen on syotial T cells, and which contrasts with the increased expression of other activation markers such as HIA-DR [9] and very late activation antigens(VL4s) [lo]. Thus, the phenotypes of T cells activated in vz’z~o in RAdiffer considerably from the phenotypes of cellsactivated in z&-o by mitogens 191.Whereas these data have been interpreted as evidence that T cells are not the driving force in synovial inflammation, they may alternatively be interpreted to mean that the T cells are indeed activated by some hitherto unidentified mechanism,but that local regulatory events have changed their phenotypes and downregulated some of their functions, for example the capacity to proliferate as well as the production of certain cytokines in vivo. Some interesting new data have also been reported concerning such putative downregulatory mechanisms.TGFp, a powerful downregulator of T-cell activation in vitro [l 11, has been found to be responsible for a large part of the T-cell inhibitory activity present in synovial fluid of RA patients [12**]. Interestingly, TGF-P has been shown to exert at least part of its action by affecting expression of IL-2 and transferrin receptors [111. Furthermore, administration of recombinant TGF-j31 to mice shortly before the onset of collagen arthritis has shown that this cytokine interferes with the effector phase of an arthritogenic response [13=*], which in the case of collagen arthritis is definitely dependent on class II-dependent T-cell activation [ 141. These data corroborate previous reports that activated macrophagescan release prostaglandin E2 in sufficiently high amounts to inhibit local T-cell activation [151.Thus, T-cell activation may be partially controlled, bearing similarities to activation seen during chronic graft rejection after cyclosporin-treated allografting, when in vivo IL-2 and IFN-y-production is greatly reduced [161,but a T-cell dependent, chronic and ultimately destructive process may still occur. If this is so, it is possible that we have to look for selected functions, i.e. selectedcytokine production rather than proliferation, and at the sametime remove certain ‘inhibitory’ events in order to discover specific T-cell reactivity using in vitro assaysfor antigen specificity of synovial T cells. Such procedures have indeed proven efficient and have given new data on autoreactivity of T cells from local lesions in multiple sclerosis [171. The second point - the lack of clearly demonstrated T-cell clonality in the joints - is diificult to discussat present as we still lack information about the the most critical point, i.e. what to expect from the human experiments performed so far if T cells representing single clones are driving the disease.Thus, the appropriate animal experiments in which cells infiltrating the target organ are analyzed by methods that may be applied in humans, have not been reported for models in which clonality of disease-inducingcells have been documented
arthritis
Klareskog,Riinnelid, Cudmundsson,Karlsson-Parra 913
convincingly (primarily EAE) [ 181.The human data accumulated so far, will be discussedin more detail below. Concerning the third, and most interesting, point - that immunosuppressantsdo not produce dramatic effects it is appropriate to make comparisonswith animal models in order to disclose what to expect from anti-T-celldirected therapies instituted at different phasesof disease development. As a result of experiments on collagen-induced arthritis in rats 1191it appears that cyclosporin A therapy may have drastic ameliorating effects when administered before the onset of disease,whereas an equally clear aggravationof the diseaseis seenif the same drug is administered a few days after the onset of symptoms. The explanation of these variable effects is not yet clear, but it may be that T cells sensitiveto cyclosporin aswell as various monoclonal antibody therapies - are involved both in elicitation of, and in protection against, the disease[ 201. Thus, for example, CD4+ T cells with the capacity to downregulate experimental collagen-induced arthritis were demonstrated recently by Myers et al. (21.1. There are two important conclusions to be drawn from these experiments. First, we cannot deny Tcell dependency of a diseaseon the basisof lack of reproducible effects on diseaseof T-cell-directed therapies used as they are today. Second, one may improve the efficacy of T-cell-directed therapies such as cyclosporin A treatment after adequate monitoring of the diseaseand better understandingwhen therapy should best be introduced. Instead of considering the lack of drastic effects of anti-T-cell-directed therapy as evidence againstthe T-cell hypothesis, we are inclined to take the accumulating data on the limited but positive effects of cyclosporin [22-a] aswell as anti-CD4 antibody therapy [23**,24**] as arguments in favour of the role of T cells in RA. Given these arguments on whether RA is T-cell driven, we will discussadvancesconcerning the details of events that regulate local T- and B-cell activation in RA, paying particular attention to events affecting specticity of local lymphocyte activation.
The trimolecular
complex
MHC class II
A structure around amino acid 70 in the P-chain of the HIA-DR molecule is important for RA susceptibility. This is described as the ‘shared epitope hypothesis’ and has been summarized previously [3]. Two setsof interesting new data have since appeared.First, the group of Nepom and collaborators [25*] have continued the structural characterization of disease-associatedDR /3-&&s and found evidence that the amino acid in position 70 is the most important, followed by those present in position 71 and 67. Furthermore, Wordsworth et af [2&l have reported structural data in favour of the ‘shared epitope hypothesis’. These findings will be important in efforts to find agentsthat can block these structures specifically. Second, a rat strain has been defined which expresses a class II molecule that possessesthis shared epitope around position 70 [27**] .. Interestingly, this rat strain was found to mount a very strong immune response to
914
Autoimmunity
human collagen type II, and to develop a very severe collagen arthritis [27**]. This finding illustrates how these rats, as well as relevant mouse transgenes, may enable us to study the functional relevance of the RA-related HIADRP substructure. Antigens,
superantigens
and
T-cell
receptors
Two strategies are obvious in the search for a putative speciIicity of the lymphocytes that may drive ti elucidation of conventional ‘candidate antigens’, and a putative bias of the TCR genes used by various T-cell populations in the rheumatoid joint. Concerning the much debated heat shock protein, the recently accumulated data have made the picture considerably more complex than before. Thus, data has accumulated recently to suggest that most reactions to hsps, both in rat and man, are directed against species-speciilc (bacterial) sequences of hsp65 rather than against sequences shared between bacteria and mammals [ 28.1. Thus, it remains to be shown whether an increased local expression of endogenous hsp60 in inflamed joints [29] constitutes part of the explanation of the perpetuation of inflammatory joint disease by hsp60reactive T cells. Interestingly, an increased T-cell reactivity to hsp60 (the human counterpart to hsp65) was recently observed [30**] in patients with juvenile RA although this reactivity was lacking in patients with advanced RA The other major group of ‘candidate antigens’ are derived from cartilage and there is now evidence for local - and probably T-cell-dependent - IgG anti-collagen II production in the joints of patients with RA [31]. Circumstantial evidence that similar reactivities may contribute to systemic manifestations of RA were provided by the demonstration of circulating antibodies to Clq in RA complicated by vasculitis [32*]; such anti-Clq antibodies may cross-react with antibodies to native collagen type II [33] and contribute to complement activation thereby, mediating systemic complement activation when present in the circulation. Interestingly, Alsalameh et al. [34] have reported increased reactivity against chondrocyte membrane proteins in lymphocytes from RA joints. It is not known, however, whether such reactivities are arthritogenic in animal systems. Superantigens have opened a major new aspect of RA research during the past few years, which bridges the questions of ‘candidate antigens’ and T-cell receptor use. Many super-antigens are of microbial origin and have the lnterestlng capacity to either activate or suppress the reactivity of T cells expressing a certain variable structure on their up (mainly p) chains (for review see [35]). Such super-antigens may trigger the activation of a large number of T cells, potentially pathogenic in RA. As most clearly formulated by Paliard et al. [3@*], a two-step procedure involving an initial action by a superantigen, followed by a self-perpetuated response to some conventional (auto)antigen might constitute the best explanation of a limited bias towards the use of T-cell receptors coded by the VP 14 family in RA synovial fluid, and the concomitant evidence for preference of certain clones within this fe. Such a notion may also provide an explanation for the Merent results concerning T-cell oligoclonality
obtained from different laboratories obtained around the world (see, for example, [37-l. It is possible that different etiologic agents are responsible for primary stimulation, which is later followed by other more uniform perpetuating events. Circumstantial evidence for this hypothesis is more limited expression of variable TCR genes seen in lymphocytes from synovial biopsies, obtained arthroscopicaiiy from RA patients with short as compared with long disease duration [38]. Future
prospects:
lessons
from
immunotherapy
Immunotherapy can be more or less selective, and it can be primarily directed towards blockade of certain functions or the induction of more permanent changes, making use of the immune system’s capacity for memory. It is likely that we will get both the best information about immunopathogenesis and the best results for patients by increased selectivity and increased use of the memory function. With today’s knowledge, the most selective therapy would be antibodies directed against arthritis-associated hlHC class II molecules; no results from such therapies are, however, yet available. The second most selective therapy appears to be blockade of various non-polymorphic T-cell structures. In a few studies, as yet mainly experimental, a new and interesting possibility has emerged for selective immunotherapy, which may obviate the need to know the specificity of pathogenic immune reactions in advance. The most promising one for clinical application again makes use of anti-CD4 antibodies, not as general blocking agents but, as a means to change the reactivity of the immune system specifically. Thus, administration of large amounts of certain anti-CD4 antibodies to block specific critical sites of the CD4 molecule while the immune system is subjected to a particular antigenic challenge, appears to induce a refractoriness (sometimes denoted immunological ‘anergy’) to further stimulation with this particular antigen [39-l. Using this procedure, it is possible to induce a specific transplantation tolerance to non-histocompatibile organs grafted under relevant antiCD4 therapy [40**]. For human diseases that result from CD4-dependent activation of specific but, so far uncharacterized, T cells against yet unknown antigen(s), the use of this CD4 blocking therapy during exacerbations of the disease is one obvious application; particularly, because during exacerbations we can assume that there is preferential activation of disease-inducing T cells. The practical implementation of this procedure obviously demands much care in selecting the anti-CD4 antibodies to be used. It would also demand empirical studies - both in man and in animals - of the effect of blocking anti-CD4 therapy instituted at different phases of disease, as well as studies on how to combine the anti-CD4 therapy with other synergistic treatments. In an initial patient with systemic vasculitis, attempt to treat with a broad depleting anti-leucocyte antibody and subsequently with anti-CD4 antibodies [41*] was successful. It is thus possible that the use of anti-CD4 therapy may represent the first practically applicable protocol that makes it possible to achieve specific Immunotherapy without first knowing the specificity of disease-inducing reactions. It is obvious that an-
Rheumatoid
alytical studies of immunoreactivities that disappear and prevail during such treatments may teach us much about the specificity of the disease-inducingreactions. References and recommended
reading
Papers of special interest, published within the annual period of review. have been highlighted as: of interest . .. of outstanding interest 1. STAYING’P: Association of the B Cell Alloantigen DRw4 with Rheumatoid Arthritis. N En@ J &d 1978. 2981863-871. 2. GK&XRSEN PK, SII.WRJ. WINCHESIXRR: The Shared Epitope Hypothesis. An Approach to Understanding the Molecular Genetics of Susceptibility to Rheumatoid Arthritis. Arlllri/ti Rheum 1987. 30:1205-1213. JANOSS~G. PANAn G, Dtllir;. 0. BOFILI. M. Pou1.711~LW. 3. ~IDSTMN G: Rheumatoid Arthritis: a Disease of T Lymphocyte/Macrophage Immunoregulation. I~~tfcc~l1981. ii:839-f%3. 4. BLIRMG~R GR. YLI D71’. IRANI AM, KIINKI~I. HK, WINCI-II~STER RJ:Ia + T Cells in Synovial Fluid and Tissue of Patients with Rheumatoid Arthritis. ArU~rilb Kbertm 1981, 24:137&1376. 5. KLkRwKOC, I, FORSUM LI. SCHEYNIIIS A, KABEIJ~Z D, WIGXU H: Evidence in Support of a Self-Perpetuating HLA-DR Dependent Delayed-Type Reaction in Rheumatoid Arthritis. Proc Nat1 Acad Sci U.S.4 1982, 79:3632-3636. FIRESTEINGS, ZVAIFLERNJ: How Important are T CelIs in Chronic Rheumatoid Synovitis? Arlhritis Rheum 1990, 33:7W773. This report challenges the role of T cells in the pathogenesis of RA,on the basis of the authors’ own data on occurrence of different cytokines in RA joints and previous data reported by others. 7. ZIECIIR 8, GAY RE, HLIANC GQ, FA~BENIXR IHG, GAY S: Immunohistochemical Localization of HTLV-I p19 and p24 Related Antigens in Synoviai Lining Cells of Patients with Rheumatoid Arthritis. Am J Pa&l 1989, 135:1-5. 8. FIRESTEIN GS, ALVARO-GARCIA JM, MAKI R: Quantitative Analysis .. of Cytokine Gene Expression in Rheumatoid Arthritis. J fmmunol 1990, 144:3347-3353. One of the papers constituting the experimental basis for questioning the role of T cells in RA f?zsitu hybridization was used to quantitate numbers of cells from RA synovial fluid and syno~ial tissue that contain mRNA encoding various cytokines. Cells producing mainly macrophagederived cytokines such as GM-CSF and n\lF.a were much more abundant than cells producing the T-cell-derived cytokine IFN-1. BURMESTERGR, JAHN 8, G~IZKI M, ZACHERJ, KALIXN JR: 9. Activated T-Cells In Viva and In Vitm Divergence in Expression of Tat and Ia Antigens in the Non-Blastoid Small T-Ceils of inflammation and the Normal T-Cells Activated In Wro. J lmmunol 1984, 133:1230-1234.
arthritis
IAFFON CLJESTA
A,
SANCHEZ-MADRID
F.
DE
LLNDAZUIU
MO,
JIMENEZ
A, ARIZAA, OS~OIUOC, SABANDOP: Very Late Activation Antigen on Synovial Fluid T Cells from Patients with Rheumatoid Arthritis and Other Rheumatic Diseases. Arth-ilis Rbeum 1909, 32~386392. 11.
KEHRLJH, WAKEFIEIDLM, ROBERTSAB, JAKO~ S, ALVAREZMON M, DERYNCKR, SPORNM, FAUCIA: Production of Transforming Growth Factor p by Human T Lymphocytes and Its Potential Role in the Regulation of T CeU Growth. / ,Eqo Med 1986, 163:1037-1050. 12. ml2 M, KEKOWJ, CARSOND: Transforming Growth Factor-P .. and Cellular Immune Responses In SynoviaI Fluids. / Irn. munol 1990. 144:4189-4194. In this study most of the functional impairment of synovial fluid T cells was neutralized by a specific antibody against TGF-P. A bioassayshowed a close correlation between immunosuppression and TGF-j3 levels in
Riinnelid,
Cudmundsson,
Karlsson-Parra
.synotial fluid. Most activityoriginated from TGF-P2 (i.e. it was of nonlymphocyte origin). CD4 + T cells were more sensitive to TGF-&me& ated suppression than CD8+ T cells. 13. K~IRL~I~A AP. SHAHR. HOCHWAIDGM, Llc&rrr HD, PAIJADINO .. MA, TI-IORIXKE GJ: Protective Effect of Transforming Growth Factor pl on Experimental Autoimmune Disease in Mice. Proc Natl Acad Sci C&4 1991, 88:2918-2921. Recombinant TGF-PI v.ds injected into mice that had been induced to develop collagen arthritis or EAE. Almost complete protection was seen in collagen arthritis and onset of disease was delayed in EAE. Interestingly, in a putative clinical perspective, it was also found that treatment with TGF-PI prevented relapses of already manifest F.AE. I?. KIARWWG I.:What Can We Learn About Rheumatoid Arthritis Erom Animal Models? Springer Sem Immunopatboi 1989, 11:315-333. IS. KIARESKCGI+ HOIMDAHLR, RUBINK. VICTORIN& LINDGREN J& Different Populations of Rheumatoid Adherent Ceils Mediate Activation vs Suppression of T-Lymphocyte ProUferation. Arlhilis Rbeum 1985, 28~863-873. 16.
DALI&W MJ. MONTGOMERY RA, LUFISEN CP, WANDERS A, WELLS AF: Cytokine Gene Expression: Analysis Using Northern Blotting, Polymerase Chain Reaction and In Situ Hybridization. lmmlrnol Ret! 1991, 119:163-179.
17.
~SKOG L. OLSON T: AutoImmunity to Collagen II and Myelin Basic Protein: Comparative Studies in Human and Rodents. lmmlrnol Ret! 1990, 118:285-310.
18.
ACHA-ORBEAH. MITCHEII.D, T~~MERMANL, WRAITHDC, TAUSCH 5, WAUXR MK, iXMVlI. SS, MCDEVI-IT HO, %I3NM4N L: Limited Heterogeneity of T CeU Receptors from Lymphocytes Mediating Autoimmune Encephalomyelitis Allows SpecUic Immune Intervention. Ceil 1988, 54~263-273.
19.
KAIBARAN, HOTOKEBLICHIT, TAKACISHIK, KATSUIUI: Paradoxical Effects of Cyclosporin A in CoUagen Arthritis in Rats. J Exp Med 1983, 158:2007-2017. LIDER 0, RESHEFT, BERAUSE, BEN-NUN A, COHEN IR: AntIldiotypic Network Induced by T Cell Vaccination Against Experimental Autoimmune Encephalomyelitis. Science 1988, 239:181-183.
6. ..
10.
Klareskog,
20.
21. .
MYERSL. STUART J, KANC A: A CD4 CeU is Capable of Transfening Suppression of Collagen Induced Arthritis. J Irn. munol 1989, 143:3976-3980. The nature of suppression ot collagen-induced arthritis caused by prior injection of collagen type 11was examined. Adoptive transfer of spleen cells from preinjected mice showed that the suppressive ceils belonged to a CD4 + , radiosensitive population of T cells, included in the pgp-l-positive memory subset. Treatment of the donor animals with cyclosporin A also abrogated suppression. 22. ..
TUGWXLL P, BOMBARDIERIC, GENT M, ET AL: Low Dose Cyclosporin vs Placebo in Patients with Rheumatoid Arthritis. Lancef 1990, 335:1051-1055. In this first controlled study of low-dose cyclosporin A in RA, 144 patients with severe RA were randomized to receive oral cyclosporin A or placebo for 6 months. Significant improvements were Found in cyclosporin A treated patients: less pain, functional status, active joints and global improvement. 23. ..
HORNEFFG. BURMES~FR GD, E~IMRICH F, KALDEN JR:Treatment of Rheumatoid Arthritis with an Anti-CD4 Monoelonal Antibody. Arthiti Rbeum 1991, 34:129-140. Ten patients with severe intractable RA were treated for 7 days with a mouse anti-human CD4 antibody. A reduction in numbers of CD4’ cells (T cells as well as macrophages) persisted for at least 2 months. Clinical improvement was seen in seven out of nine patients after 1 or a few weeks and lasted up to 6 months. Also the erythrocyte sedImentation rate (ESR), rheumatoid factor (RF) titers and C reactive protein (CRP) were reduced in most patients and adverse effectswere modest
24. ..
REITER C, KAKAVANDB, RIEBER EP, SCHXITENKIRCHNER M, RIETMuuER G, KRUGERK: Treatment of Rheumatoid Arthritis with MonoclonaI CD4 AntIbody M-T151. Ar&ihZs Rbeum 1991, 34:525-536.
915
916
Autoimmunity The patients were treated for 7 consecutive days with a mouse antihuman CD4 antibody. A clinical improvement was seen in six out of 10 patients that lasted 4-6 months. In these patien& CRP. but not ESR and RF, decreased with the therapy. Although initially depleted, CD4+ T cells were reported to return to normal 24 h after each infusion.
25.
H~RANYA A, YAMANA~~A K, KWOK W, MICKEIS~N E, MA~RWICZ S. HANSEN J, RA~KA S, NEI’OM G: Structural Requirements for Recognition of the HLA-Dwl4 class I Epitope: a Key HLA Determinant Associated with Rheumatoid Arthritis. Proc Nat1 Acad Sci UU 1990, 87:8051-8055. Site-directed mutagenesis of the DRBI gene was used to define the amino acids that are most crltlcal for T-cell recognition, focusing on the residues that distinguish Dw4 and Dw14 (RA associated) from DwlO (no association). The relative importance of different residues for recognition within the shared epitope was established, and correlated with gain and loss of RA association.
.
26.
Woaoswoto~ BP, IANCHBURY JSS. QKKAS Ll, WEUH Kl. PANA~I GS, BELL Jl: HLA-DR4 Subtype Frequencies in Rheumatoid Arthritis Indicate that DRBl is the Major Susceptibility Locus within the HLA Class II Region. Proc Nat1 Acad Sci LISA 1989. 86:10049-10053. This paper reports evidence to further support the shared epitope hypothesis. Sequencing DRBl and DQBl genes from more than 150 RA patients showed a highly conserved epitope in DR4 and DRl haplotypes on RA patients. .
27.
WATSON WC, THOMPSON JP, TER~TO K, CREhieR M, KANc A Human HLA-DRB Gene Hypervariable Region Homology in the Biobreediig BB Rat: Selection of the Diabetic-Resistant Subline as a Rheumatoid Arthritis Research Tool to Characterize the Immunopathologic Response to Human Type II Collagen. J Exp Med 1990, 172:1331-1339. The BB tat, mostly used as a research tool in diabetes, was selected because of its human susceptibility sequence in the third hypervarlable region of the RTl DB gene. A diabetic-resistant subline was selected, and immunized with human coUagen type II. An aggressive form of arthritis developed in all the animals.
..
ALS~~A~~EH S. MOUENHAUER J. HAIN N, STOCK KP. KALDEN J. B~IR~~ES~R G: Cellular Immune Response Toward Human Articular Chondrocytcs. Arlhrifb f&ero?r 1990. 33: I477I&6. T-cell reacti\iry against chondro+e membranes wts found among s>n ovial fluid ‘and peripheral blood cells from RA patients ils well as pa tients with osteoarthritis. The results are highly interesting, refocusing the interest in tissue-specific autoimmune reactions from those in the extmcellular matrix. which have hitherto been studied, to other cartlage molecules.
34. .
35.
GA~TON J, LIFE P, JENNER P, COL~TON M, BACON P: Recognition of a Mycobacteria-Specific Epitope ln the 65-kD Heat-Shock Protein by Synovial-Ruid-Derived T Cell Clones. J Exp Med 1990, 171:831-841. This study reports synovial fluid CD4+, CIXTCR aB+ T-ceU clones that recognize a mycobacterlal hsp65 epitope that is not conserved between bacteria and eukaryotes.
29.
KARLSSON-PARRA A, SODERS~ROM K, FERM M, IVAN J, K~ESSUNC R, KLUtEsKoG L Presence of Human 65kD Heat Shock Protein in Infhtmed Joints and Subcutaneous Nodules of RA patients. &and J lmmunol 1990, 32:503-525.
DE GRAEFF-MEEDER ER, VAN DER ZEE R, R~JKERS GT, SCHUURMAN HJ, KUIS W, BIJ~%~A JWJ, ZECER~ BJM, VAN EDEN W: Recognition of Human 6OkD Heat Shock Protein by Mononuclear CeJls from Patients with Juvenile Chronic Arthritis. Lancet 1991, 33X1368-1372. T-cell reactivity against recombinant human hsp60 was observed in patients with active juvenile chronic arthritis, but not in adult patients with advanced, erosive RA.
30. ..
31.
T~tttcowsto A, K~ARE~KOG L, CARLSIFN H, HERBERTS P, KOOPMAN WJ: Secretion of AntIbodies to Types I and II Collagen by SynovIaI Tissue CelIs in Patients with Rheumatoid Arthritis. Artbriti Rbeum 1989, 32:1087-1096.
SIEGERT C, DABA M, VAN DER VOORT E, BREEDVELD F: IgG and IgA AntibodIes to the CoIIagen-Like Region of Clq in Rheumatoid Vasculitis. Arhritk Rbeum 1990, 3316461654. This study demonstrates that sera from patients with rheumatoid MSct.&is frequently contain IgG and IgA antibodies against the collagenlike region of Clq. These antibodies may contribute both to immune complex formation and to complement activation.
32.
.
33.
HEtNZ topes
HB, RtmtN K, IAUREU In Clq and Collagen
26:163169.
AB, Type
LOOS M: Common II. Mol Immunol
Epi1989,
Enterotoxins
and
PAUARD x, wm SG. ~FIWU-Y ~4 cLEhlENIS JR. Kmui~ .w, MARRACK P, K~‘IZIN BL Evidence for the Effects of a Superantigen in Rheumatoid Arthritis. Scie?rce 1991, 253:325-329. Using a polymerase chain reaction based technique for quantitation of mRNA for various TCR variable segments in s~novial fluid and periph. et-al blood of RA patients, the estimated frequency of V81-lf T cells was found to be significantly lower in the periphery than in the qnovlum. Sequence Rnalysis suggested that clonal expansion had taken place within the VB14+ synovial T-cell population,
36. ..
37. .
Smm stricted Genes
A IMI~ERTI L, GORV\ R. CATMNEO R. PixthtI D: ReExoression of T Ceil Receptor Vg but not Va in Rheumatoid Arthritis. Ettr J fmrrzr~trol 1991,
21:61d6. The polymerase chain reaction was used to estimate the relative fre. quency of different Va and V8 elements in .synovial fluid and peripheml blood lymphocytes of three RA patients. Only a few VP transcripts were used - preferentially V87. but not VP14 - whereas no restriction was seen among the Va elements.
38.
BUCHT A, OKSENBERG J, LINDB~ S, GRONB~RG A, STEiNhlNrl L, KIARESK~C L Characterization of T CelI Receptor Repertoire in Synovial Tissue from Different Temporal Phases of Rheumatoid Arthritis. ScandJ Immunol 1991, in press.
39.
QIN S. WISE M, COBBOID S, LEONG L, KONG Y, PARNES J. WALDMANN H: Induction of Tolerance in Peripheral T Cells with Monoclonal Antibodies. Eztr J fnun~nol 1990,
.
28. .
M~ret~c:~ P. KAPPLER J: The Staphylococcal Their Relatives. Scie~rce I99Q. 248:32%329.
20:2737-2745. Using selected antiCD4 antibodies it was possible to render postthymic T cells of mice tolerant to a range of antigens (human and rat immunoglobulins as well as bone marrow and skin grafts differing from the host at multiple minor histocompatibility antigens). In the cases of human gammaglobulin, tolerance was obtained after antigen was given under the cover of a short course of non-depleting anti-CD4 antibodies. For skin and bone marrow gtafts administration of anti-CD8 antibodies was also required to achieve tolerance.
40.
COBBOLD S, MAR~N G, WAU)~WNN H: The Induction of Skin Graft Tolerance in Major Histocompatibility Complex-Mismatched or Primed Recipients: Primed T Cells can be Tolerized in the Periphery with Anti-CD4 and Anti-CD8 Antibodies. Eur J Immunol 1990, 20~2747-2755. This report shows that tolerance to allogeneic skin grafted at the time of antibody administration can be obtained after administration of blocking anti-CD4 anti-CD8 antibodies in both naive and primed animals. The demonstration of tolerance induction in the case of a primed host has important implications for Further development of human therapy. ..
41.
MA-MESON P, COBBOUI S, HALE G, CLARK M, O~MERA D, LOXWOOD C, WAU)MANN H: Monoclonal Antibody Therapy In Systemic VascuIitls. N Engl J Med 1990, 323:250-254. The humanized antibody Campath-1H and later an anti-CD4 antibody were administered, in the hope that an initial depletion of the bulk of lymphocytes with Campath-lH, and subsequent application of anti-CD4 would induce tolerance to putative autoantigens of pathogenetic impor. tance. A remission was induced that had lasted 12 months when the article was published. .
L Klareskog, of Clinical Sweden.
J RonneUd, Immunology,
S Gudrnundsson, S-751 85 Uppsala
A Karlsson-Parm, Department University Hospital, Uppsala,
Johan
Rbnelid,
Alex Uppsala
arthritis Sveinn
Cudmundsson
and
Karlsson-Parra
University,
Uppsala,
Sweden
The immunopathogenesis of rheumatoid arthritis is discussed in two ways. First, we consider the major question of whether T cells are likely to drive the disease. Second - and assuming T cells to be important we discuss available data on the components of the trimolecular complex (major histocompatibility complex class II-antigen-T-cell receptor), which are possibly involved in the disease. Our two main points are that the most important questions concerning the pathogenesis of rheumatoid arthritis require answers from immunointervention in patients, and that animal experiments can be increasingly used in interpreting current experiments in humans.
Current
Opinion
in Immunology
Introduction Rheumatoid arthritis (RA) is a diseasethat is mainly deiined by clinical criteria, in which systematicpathogenetic studies have been hampered by doubts about the presence of common pathogenetic mechanismsand the relative lack of unique laboratory findings. The two major observationsthat have altered this situation, and have deiined the present direction of research, are the demon stration of a lInkage between certain major histocompatibillty complex (MIX) classII allelesand diseasesusceptibility [ 1,2], and elucidation of the cellular events within the inilammatory lesions, primarily in the joints, which has led to suggestionsthat local MHC classII-dependent T-cell activation is the primary driving force in development of disease[35]. This review will focus on two major issuesconcerning our understanding of RA. We will discusswhether T-celldriven immune reactions are essentialin RA and, assuming such T-cell reactions are important, the components of the trimolecular complex (MIX classIIantigen-T-cell receptor) that determine the specificity of the putative arthrltogenic T-cell reactivities. In our attempts to discuss both these issues,we must consider the fact that only immunological intervention in RA patients can determine conclusively whether an immunological event is a driving force in the disease,or merely representsan epiphenomenon.
1991, 3:912-916
Driving forces in arthritis: evidence and aganist MHC class II-dependent activation
Although a role for T-cell activation in the pathogenesisof RA is assumedin both analytical and therapeutic studies, this assumption is still controversial. Thus, it is essential to heed all data reported that challenge this fundamental point. Recently, Firestein and Zvaifler [6**] questioned the role of T cells on the basis of three observations. First, the relative lack of certain characteristicsof activation in synovial T cells: particularly the lack of proliferation and low production of cytokines by T cells, compared with high cytokine production by macrophages. Second, the lack of clear evidence for clonal expansion of T cellsin the joint. Third, the lack of dramatic effects of drugs such ascyclosporin A, which affect T-cell activation. These points must be seriously considered by workers such as ourselves who maintain that the T-cell hypothesis is the most viable. A failure to counter these proposals would imply the need to search for mechanisms,for example virus-dependent events, that may causetransformation and proliferation of synovial cells without stimuli from activated T cells [7]. The first point- the lack of synovial T-cell activation - has been studied experimentally by Zavaifler and Firestein’s groups. Evidence of a relatively low synovial production of T-cell cytokines such as interleukin (IL)-2
Abbreviations CRP-C-reactive protein; ESR-erythrocyte sedimentation rate; GM-CS~ranulocyte-macrophage colony-stimulating factor; IFN-interferon; MHC-major RA-rheumatoid arthritis; R&rheumatoid factor; TN&tumor necrosis
912
(EJ Current
Biology
for T-cell
Ltd ISSN
0952-7915
histocompatibility factor.
complex;
Rheumatoid
and interferon (IFNI-y and high production of cytokines such as tumor necrosis factor (TNF)-a and granulocytemarcophage colony-stimulating factor (GM-CSF), which are mainly produced by activated macrophages,hasbeen reported [@*I. There have also been reports of very limited T-cell proliferative activity within the joints [6-l, a feature compatible with the relatively low IL-2 receptor expression that is seen on syotial T cells, and which contrasts with the increased expression of other activation markers such as HIA-DR [9] and very late activation antigens(VL4s) [lo]. Thus, the phenotypes of T cells activated in vz’z~o in RAdiffer considerably from the phenotypes of cellsactivated in z&-o by mitogens 191.Whereas these data have been interpreted as evidence that T cells are not the driving force in synovial inflammation, they may alternatively be interpreted to mean that the T cells are indeed activated by some hitherto unidentified mechanism,but that local regulatory events have changed their phenotypes and downregulated some of their functions, for example the capacity to proliferate as well as the production of certain cytokines in vivo. Some interesting new data have also been reported concerning such putative downregulatory mechanisms.TGFp, a powerful downregulator of T-cell activation in vitro [l 11, has been found to be responsible for a large part of the T-cell inhibitory activity present in synovial fluid of RA patients [12**]. Interestingly, TGF-P has been shown to exert at least part of its action by affecting expression of IL-2 and transferrin receptors [111. Furthermore, administration of recombinant TGF-j31 to mice shortly before the onset of collagen arthritis has shown that this cytokine interferes with the effector phase of an arthritogenic response [13=*], which in the case of collagen arthritis is definitely dependent on class II-dependent T-cell activation [ 141. These data corroborate previous reports that activated macrophagescan release prostaglandin E2 in sufficiently high amounts to inhibit local T-cell activation [151.Thus, T-cell activation may be partially controlled, bearing similarities to activation seen during chronic graft rejection after cyclosporin-treated allografting, when in vivo IL-2 and IFN-y-production is greatly reduced [161,but a T-cell dependent, chronic and ultimately destructive process may still occur. If this is so, it is possible that we have to look for selected functions, i.e. selectedcytokine production rather than proliferation, and at the sametime remove certain ‘inhibitory’ events in order to discover specific T-cell reactivity using in vitro assaysfor antigen specificity of synovial T cells. Such procedures have indeed proven efficient and have given new data on autoreactivity of T cells from local lesions in multiple sclerosis [171. The second point - the lack of clearly demonstrated T-cell clonality in the joints - is diificult to discussat present as we still lack information about the the most critical point, i.e. what to expect from the human experiments performed so far if T cells representing single clones are driving the disease.Thus, the appropriate animal experiments in which cells infiltrating the target organ are analyzed by methods that may be applied in humans, have not been reported for models in which clonality of disease-inducingcells have been documented
arthritis
Klareskog,Riinnelid, Cudmundsson,Karlsson-Parra 913
convincingly (primarily EAE) [ 181.The human data accumulated so far, will be discussedin more detail below. Concerning the third, and most interesting, point - that immunosuppressantsdo not produce dramatic effects it is appropriate to make comparisonswith animal models in order to disclose what to expect from anti-T-celldirected therapies instituted at different phasesof disease development. As a result of experiments on collagen-induced arthritis in rats 1191it appears that cyclosporin A therapy may have drastic ameliorating effects when administered before the onset of disease,whereas an equally clear aggravationof the diseaseis seenif the same drug is administered a few days after the onset of symptoms. The explanation of these variable effects is not yet clear, but it may be that T cells sensitiveto cyclosporin aswell as various monoclonal antibody therapies - are involved both in elicitation of, and in protection against, the disease[ 201. Thus, for example, CD4+ T cells with the capacity to downregulate experimental collagen-induced arthritis were demonstrated recently by Myers et al. (21.1. There are two important conclusions to be drawn from these experiments. First, we cannot deny Tcell dependency of a diseaseon the basisof lack of reproducible effects on diseaseof T-cell-directed therapies used as they are today. Second, one may improve the efficacy of T-cell-directed therapies such as cyclosporin A treatment after adequate monitoring of the diseaseand better understandingwhen therapy should best be introduced. Instead of considering the lack of drastic effects of anti-T-cell-directed therapy as evidence againstthe T-cell hypothesis, we are inclined to take the accumulating data on the limited but positive effects of cyclosporin [22-a] aswell as anti-CD4 antibody therapy [23**,24**] as arguments in favour of the role of T cells in RA. Given these arguments on whether RA is T-cell driven, we will discussadvancesconcerning the details of events that regulate local T- and B-cell activation in RA, paying particular attention to events affecting specticity of local lymphocyte activation.
The trimolecular
complex
MHC class II
A structure around amino acid 70 in the P-chain of the HIA-DR molecule is important for RA susceptibility. This is described as the ‘shared epitope hypothesis’ and has been summarized previously [3]. Two setsof interesting new data have since appeared.First, the group of Nepom and collaborators [25*] have continued the structural characterization of disease-associatedDR /3-&&s and found evidence that the amino acid in position 70 is the most important, followed by those present in position 71 and 67. Furthermore, Wordsworth et af [2&l have reported structural data in favour of the ‘shared epitope hypothesis’. These findings will be important in efforts to find agentsthat can block these structures specifically. Second, a rat strain has been defined which expresses a class II molecule that possessesthis shared epitope around position 70 [27**] .. Interestingly, this rat strain was found to mount a very strong immune response to
914
Autoimmunity
human collagen type II, and to develop a very severe collagen arthritis [27**]. This finding illustrates how these rats, as well as relevant mouse transgenes, may enable us to study the functional relevance of the RA-related HIADRP substructure. Antigens,
superantigens
and
T-cell
receptors
Two strategies are obvious in the search for a putative speciIicity of the lymphocytes that may drive ti elucidation of conventional ‘candidate antigens’, and a putative bias of the TCR genes used by various T-cell populations in the rheumatoid joint. Concerning the much debated heat shock protein, the recently accumulated data have made the picture considerably more complex than before. Thus, data has accumulated recently to suggest that most reactions to hsps, both in rat and man, are directed against species-speciilc (bacterial) sequences of hsp65 rather than against sequences shared between bacteria and mammals [ 28.1. Thus, it remains to be shown whether an increased local expression of endogenous hsp60 in inflamed joints [29] constitutes part of the explanation of the perpetuation of inflammatory joint disease by hsp60reactive T cells. Interestingly, an increased T-cell reactivity to hsp60 (the human counterpart to hsp65) was recently observed [30**] in patients with juvenile RA although this reactivity was lacking in patients with advanced RA The other major group of ‘candidate antigens’ are derived from cartilage and there is now evidence for local - and probably T-cell-dependent - IgG anti-collagen II production in the joints of patients with RA [31]. Circumstantial evidence that similar reactivities may contribute to systemic manifestations of RA were provided by the demonstration of circulating antibodies to Clq in RA complicated by vasculitis [32*]; such anti-Clq antibodies may cross-react with antibodies to native collagen type II [33] and contribute to complement activation thereby, mediating systemic complement activation when present in the circulation. Interestingly, Alsalameh et al. [34] have reported increased reactivity against chondrocyte membrane proteins in lymphocytes from RA joints. It is not known, however, whether such reactivities are arthritogenic in animal systems. Superantigens have opened a major new aspect of RA research during the past few years, which bridges the questions of ‘candidate antigens’ and T-cell receptor use. Many super-antigens are of microbial origin and have the lnterestlng capacity to either activate or suppress the reactivity of T cells expressing a certain variable structure on their up (mainly p) chains (for review see [35]). Such super-antigens may trigger the activation of a large number of T cells, potentially pathogenic in RA. As most clearly formulated by Paliard et al. [3@*], a two-step procedure involving an initial action by a superantigen, followed by a self-perpetuated response to some conventional (auto)antigen might constitute the best explanation of a limited bias towards the use of T-cell receptors coded by the VP 14 family in RA synovial fluid, and the concomitant evidence for preference of certain clones within this fe. Such a notion may also provide an explanation for the Merent results concerning T-cell oligoclonality
obtained from different laboratories obtained around the world (see, for example, [37-l. It is possible that different etiologic agents are responsible for primary stimulation, which is later followed by other more uniform perpetuating events. Circumstantial evidence for this hypothesis is more limited expression of variable TCR genes seen in lymphocytes from synovial biopsies, obtained arthroscopicaiiy from RA patients with short as compared with long disease duration [38]. Future
prospects:
lessons
from
immunotherapy
Immunotherapy can be more or less selective, and it can be primarily directed towards blockade of certain functions or the induction of more permanent changes, making use of the immune system’s capacity for memory. It is likely that we will get both the best information about immunopathogenesis and the best results for patients by increased selectivity and increased use of the memory function. With today’s knowledge, the most selective therapy would be antibodies directed against arthritis-associated hlHC class II molecules; no results from such therapies are, however, yet available. The second most selective therapy appears to be blockade of various non-polymorphic T-cell structures. In a few studies, as yet mainly experimental, a new and interesting possibility has emerged for selective immunotherapy, which may obviate the need to know the specificity of pathogenic immune reactions in advance. The most promising one for clinical application again makes use of anti-CD4 antibodies, not as general blocking agents but, as a means to change the reactivity of the immune system specifically. Thus, administration of large amounts of certain anti-CD4 antibodies to block specific critical sites of the CD4 molecule while the immune system is subjected to a particular antigenic challenge, appears to induce a refractoriness (sometimes denoted immunological ‘anergy’) to further stimulation with this particular antigen [39-l. Using this procedure, it is possible to induce a specific transplantation tolerance to non-histocompatibile organs grafted under relevant antiCD4 therapy [40**]. For human diseases that result from CD4-dependent activation of specific but, so far uncharacterized, T cells against yet unknown antigen(s), the use of this CD4 blocking therapy during exacerbations of the disease is one obvious application; particularly, because during exacerbations we can assume that there is preferential activation of disease-inducing T cells. The practical implementation of this procedure obviously demands much care in selecting the anti-CD4 antibodies to be used. It would also demand empirical studies - both in man and in animals - of the effect of blocking anti-CD4 therapy instituted at different phases of disease, as well as studies on how to combine the anti-CD4 therapy with other synergistic treatments. In an initial patient with systemic vasculitis, attempt to treat with a broad depleting anti-leucocyte antibody and subsequently with anti-CD4 antibodies [41*] was successful. It is thus possible that the use of anti-CD4 therapy may represent the first practically applicable protocol that makes it possible to achieve specific Immunotherapy without first knowing the specificity of disease-inducing reactions. It is obvious that an-
Rheumatoid
alytical studies of immunoreactivities that disappear and prevail during such treatments may teach us much about the specificity of the disease-inducingreactions. References and recommended
reading
Papers of special interest, published within the annual period of review. have been highlighted as: of interest . .. of outstanding interest 1. STAYING’P: Association of the B Cell Alloantigen DRw4 with Rheumatoid Arthritis. N En@ J &d 1978. 2981863-871. 2. GK&XRSEN PK, SII.WRJ. WINCHESIXRR: The Shared Epitope Hypothesis. An Approach to Understanding the Molecular Genetics of Susceptibility to Rheumatoid Arthritis. Arlllri/ti Rheum 1987. 30:1205-1213. JANOSS~G. PANAn G, Dtllir;. 0. BOFILI. M. Pou1.711~LW. 3. ~IDSTMN G: Rheumatoid Arthritis: a Disease of T Lymphocyte/Macrophage Immunoregulation. I~~tfcc~l1981. ii:839-f%3. 4. BLIRMG~R GR. YLI D71’. IRANI AM, KIINKI~I. HK, WINCI-II~STER RJ:Ia + T Cells in Synovial Fluid and Tissue of Patients with Rheumatoid Arthritis. ArU~rilb Kbertm 1981, 24:137&1376. 5. KLkRwKOC, I, FORSUM LI. SCHEYNIIIS A, KABEIJ~Z D, WIGXU H: Evidence in Support of a Self-Perpetuating HLA-DR Dependent Delayed-Type Reaction in Rheumatoid Arthritis. Proc Nat1 Acad Sci U.S.4 1982, 79:3632-3636. FIRESTEINGS, ZVAIFLERNJ: How Important are T CelIs in Chronic Rheumatoid Synovitis? Arlhritis Rheum 1990, 33:7W773. This report challenges the role of T cells in the pathogenesis of RA,on the basis of the authors’ own data on occurrence of different cytokines in RA joints and previous data reported by others. 7. ZIECIIR 8, GAY RE, HLIANC GQ, FA~BENIXR IHG, GAY S: Immunohistochemical Localization of HTLV-I p19 and p24 Related Antigens in Synoviai Lining Cells of Patients with Rheumatoid Arthritis. Am J Pa&l 1989, 135:1-5. 8. FIRESTEIN GS, ALVARO-GARCIA JM, MAKI R: Quantitative Analysis .. of Cytokine Gene Expression in Rheumatoid Arthritis. J fmmunol 1990, 144:3347-3353. One of the papers constituting the experimental basis for questioning the role of T cells in RA f?zsitu hybridization was used to quantitate numbers of cells from RA synovial fluid and syno~ial tissue that contain mRNA encoding various cytokines. Cells producing mainly macrophagederived cytokines such as GM-CSF and n\lF.a were much more abundant than cells producing the T-cell-derived cytokine IFN-1. BURMESTERGR, JAHN 8, G~IZKI M, ZACHERJ, KALIXN JR: 9. Activated T-Cells In Viva and In Vitm Divergence in Expression of Tat and Ia Antigens in the Non-Blastoid Small T-Ceils of inflammation and the Normal T-Cells Activated In Wro. J lmmunol 1984, 133:1230-1234.
arthritis
IAFFON CLJESTA
A,
SANCHEZ-MADRID
F.
DE
LLNDAZUIU
MO,
JIMENEZ
A, ARIZAA, OS~OIUOC, SABANDOP: Very Late Activation Antigen on Synovial Fluid T Cells from Patients with Rheumatoid Arthritis and Other Rheumatic Diseases. Arth-ilis Rbeum 1909, 32~386392. 11.
KEHRLJH, WAKEFIEIDLM, ROBERTSAB, JAKO~ S, ALVAREZMON M, DERYNCKR, SPORNM, FAUCIA: Production of Transforming Growth Factor p by Human T Lymphocytes and Its Potential Role in the Regulation of T CeU Growth. / ,Eqo Med 1986, 163:1037-1050. 12. ml2 M, KEKOWJ, CARSOND: Transforming Growth Factor-P .. and Cellular Immune Responses In SynoviaI Fluids. / Irn. munol 1990. 144:4189-4194. In this study most of the functional impairment of synovial fluid T cells was neutralized by a specific antibody against TGF-P. A bioassayshowed a close correlation between immunosuppression and TGF-j3 levels in
Riinnelid,
Cudmundsson,
Karlsson-Parra
.synotial fluid. Most activityoriginated from TGF-P2 (i.e. it was of nonlymphocyte origin). CD4 + T cells were more sensitive to TGF-&me& ated suppression than CD8+ T cells. 13. K~IRL~I~A AP. SHAHR. HOCHWAIDGM, Llc&rrr HD, PAIJADINO .. MA, TI-IORIXKE GJ: Protective Effect of Transforming Growth Factor pl on Experimental Autoimmune Disease in Mice. Proc Natl Acad Sci C&4 1991, 88:2918-2921. Recombinant TGF-PI v.ds injected into mice that had been induced to develop collagen arthritis or EAE. Almost complete protection was seen in collagen arthritis and onset of disease was delayed in EAE. Interestingly, in a putative clinical perspective, it was also found that treatment with TGF-PI prevented relapses of already manifest F.AE. I?. KIARWWG I.:What Can We Learn About Rheumatoid Arthritis Erom Animal Models? Springer Sem Immunopatboi 1989, 11:315-333. IS. KIARESKCGI+ HOIMDAHLR, RUBINK. VICTORIN& LINDGREN J& Different Populations of Rheumatoid Adherent Ceils Mediate Activation vs Suppression of T-Lymphocyte ProUferation. Arlhilis Rbeum 1985, 28~863-873. 16.
DALI&W MJ. MONTGOMERY RA, LUFISEN CP, WANDERS A, WELLS AF: Cytokine Gene Expression: Analysis Using Northern Blotting, Polymerase Chain Reaction and In Situ Hybridization. lmmlrnol Ret! 1991, 119:163-179.
17.
~SKOG L. OLSON T: AutoImmunity to Collagen II and Myelin Basic Protein: Comparative Studies in Human and Rodents. lmmlrnol Ret! 1990, 118:285-310.
18.
ACHA-ORBEAH. MITCHEII.D, T~~MERMANL, WRAITHDC, TAUSCH 5, WAUXR MK, iXMVlI. SS, MCDEVI-IT HO, %I3NM4N L: Limited Heterogeneity of T CeU Receptors from Lymphocytes Mediating Autoimmune Encephalomyelitis Allows SpecUic Immune Intervention. Ceil 1988, 54~263-273.
19.
KAIBARAN, HOTOKEBLICHIT, TAKACISHIK, KATSUIUI: Paradoxical Effects of Cyclosporin A in CoUagen Arthritis in Rats. J Exp Med 1983, 158:2007-2017. LIDER 0, RESHEFT, BERAUSE, BEN-NUN A, COHEN IR: AntIldiotypic Network Induced by T Cell Vaccination Against Experimental Autoimmune Encephalomyelitis. Science 1988, 239:181-183.
6. ..
10.
Klareskog,
20.
21. .
MYERSL. STUART J, KANC A: A CD4 CeU is Capable of Transfening Suppression of Collagen Induced Arthritis. J Irn. munol 1989, 143:3976-3980. The nature of suppression ot collagen-induced arthritis caused by prior injection of collagen type 11was examined. Adoptive transfer of spleen cells from preinjected mice showed that the suppressive ceils belonged to a CD4 + , radiosensitive population of T cells, included in the pgp-l-positive memory subset. Treatment of the donor animals with cyclosporin A also abrogated suppression. 22. ..
TUGWXLL P, BOMBARDIERIC, GENT M, ET AL: Low Dose Cyclosporin vs Placebo in Patients with Rheumatoid Arthritis. Lancef 1990, 335:1051-1055. In this first controlled study of low-dose cyclosporin A in RA, 144 patients with severe RA were randomized to receive oral cyclosporin A or placebo for 6 months. Significant improvements were Found in cyclosporin A treated patients: less pain, functional status, active joints and global improvement. 23. ..
HORNEFFG. BURMES~FR GD, E~IMRICH F, KALDEN JR:Treatment of Rheumatoid Arthritis with an Anti-CD4 Monoelonal Antibody. Arthiti Rbeum 1991, 34:129-140. Ten patients with severe intractable RA were treated for 7 days with a mouse anti-human CD4 antibody. A reduction in numbers of CD4’ cells (T cells as well as macrophages) persisted for at least 2 months. Clinical improvement was seen in seven out of nine patients after 1 or a few weeks and lasted up to 6 months. Also the erythrocyte sedImentation rate (ESR), rheumatoid factor (RF) titers and C reactive protein (CRP) were reduced in most patients and adverse effectswere modest
24. ..
REITER C, KAKAVANDB, RIEBER EP, SCHXITENKIRCHNER M, RIETMuuER G, KRUGERK: Treatment of Rheumatoid Arthritis with MonoclonaI CD4 AntIbody M-T151. Ar&ihZs Rbeum 1991, 34:525-536.
915
916
Autoimmunity The patients were treated for 7 consecutive days with a mouse antihuman CD4 antibody. A clinical improvement was seen in six out of 10 patients that lasted 4-6 months. In these patien& CRP. but not ESR and RF, decreased with the therapy. Although initially depleted, CD4+ T cells were reported to return to normal 24 h after each infusion.
25.
H~RANYA A, YAMANA~~A K, KWOK W, MICKEIS~N E, MA~RWICZ S. HANSEN J, RA~KA S, NEI’OM G: Structural Requirements for Recognition of the HLA-Dwl4 class I Epitope: a Key HLA Determinant Associated with Rheumatoid Arthritis. Proc Nat1 Acad Sci UU 1990, 87:8051-8055. Site-directed mutagenesis of the DRBI gene was used to define the amino acids that are most crltlcal for T-cell recognition, focusing on the residues that distinguish Dw4 and Dw14 (RA associated) from DwlO (no association). The relative importance of different residues for recognition within the shared epitope was established, and correlated with gain and loss of RA association.
.
26.
Woaoswoto~ BP, IANCHBURY JSS. QKKAS Ll, WEUH Kl. PANA~I GS, BELL Jl: HLA-DR4 Subtype Frequencies in Rheumatoid Arthritis Indicate that DRBl is the Major Susceptibility Locus within the HLA Class II Region. Proc Nat1 Acad Sci LISA 1989. 86:10049-10053. This paper reports evidence to further support the shared epitope hypothesis. Sequencing DRBl and DQBl genes from more than 150 RA patients showed a highly conserved epitope in DR4 and DRl haplotypes on RA patients. .
27.
WATSON WC, THOMPSON JP, TER~TO K, CREhieR M, KANc A Human HLA-DRB Gene Hypervariable Region Homology in the Biobreediig BB Rat: Selection of the Diabetic-Resistant Subline as a Rheumatoid Arthritis Research Tool to Characterize the Immunopathologic Response to Human Type II Collagen. J Exp Med 1990, 172:1331-1339. The BB tat, mostly used as a research tool in diabetes, was selected because of its human susceptibility sequence in the third hypervarlable region of the RTl DB gene. A diabetic-resistant subline was selected, and immunized with human coUagen type II. An aggressive form of arthritis developed in all the animals.
..
ALS~~A~~EH S. MOUENHAUER J. HAIN N, STOCK KP. KALDEN J. B~IR~~ES~R G: Cellular Immune Response Toward Human Articular Chondrocytcs. Arlhrifb f&ero?r 1990. 33: I477I&6. T-cell reacti\iry against chondro+e membranes wts found among s>n ovial fluid ‘and peripheral blood cells from RA patients ils well as pa tients with osteoarthritis. The results are highly interesting, refocusing the interest in tissue-specific autoimmune reactions from those in the extmcellular matrix. which have hitherto been studied, to other cartlage molecules.
34. .
35.
GA~TON J, LIFE P, JENNER P, COL~TON M, BACON P: Recognition of a Mycobacteria-Specific Epitope ln the 65-kD Heat-Shock Protein by Synovial-Ruid-Derived T Cell Clones. J Exp Med 1990, 171:831-841. This study reports synovial fluid CD4+, CIXTCR aB+ T-ceU clones that recognize a mycobacterlal hsp65 epitope that is not conserved between bacteria and eukaryotes.
29.
KARLSSON-PARRA A, SODERS~ROM K, FERM M, IVAN J, K~ESSUNC R, KLUtEsKoG L Presence of Human 65kD Heat Shock Protein in Infhtmed Joints and Subcutaneous Nodules of RA patients. &and J lmmunol 1990, 32:503-525.
DE GRAEFF-MEEDER ER, VAN DER ZEE R, R~JKERS GT, SCHUURMAN HJ, KUIS W, BIJ~%~A JWJ, ZECER~ BJM, VAN EDEN W: Recognition of Human 6OkD Heat Shock Protein by Mononuclear CeJls from Patients with Juvenile Chronic Arthritis. Lancet 1991, 33X1368-1372. T-cell reactivity against recombinant human hsp60 was observed in patients with active juvenile chronic arthritis, but not in adult patients with advanced, erosive RA.
30. ..
31.
T~tttcowsto A, K~ARE~KOG L, CARLSIFN H, HERBERTS P, KOOPMAN WJ: Secretion of AntIbodies to Types I and II Collagen by SynovIaI Tissue CelIs in Patients with Rheumatoid Arthritis. Artbriti Rbeum 1989, 32:1087-1096.
SIEGERT C, DABA M, VAN DER VOORT E, BREEDVELD F: IgG and IgA AntibodIes to the CoIIagen-Like Region of Clq in Rheumatoid Vasculitis. Arhritk Rbeum 1990, 3316461654. This study demonstrates that sera from patients with rheumatoid MSct.&is frequently contain IgG and IgA antibodies against the collagenlike region of Clq. These antibodies may contribute both to immune complex formation and to complement activation.
32.
.
33.
HEtNZ topes
HB, RtmtN K, IAUREU In Clq and Collagen
26:163169.
AB, Type
LOOS M: Common II. Mol Immunol
Epi1989,
Enterotoxins
and
PAUARD x, wm SG. ~FIWU-Y ~4 cLEhlENIS JR. Kmui~ .w, MARRACK P, K~‘IZIN BL Evidence for the Effects of a Superantigen in Rheumatoid Arthritis. Scie?rce 1991, 253:325-329. Using a polymerase chain reaction based technique for quantitation of mRNA for various TCR variable segments in s~novial fluid and periph. et-al blood of RA patients, the estimated frequency of V81-lf T cells was found to be significantly lower in the periphery than in the qnovlum. Sequence Rnalysis suggested that clonal expansion had taken place within the VB14+ synovial T-cell population,
36. ..
37. .
Smm stricted Genes
A IMI~ERTI L, GORV\ R. CATMNEO R. PixthtI D: ReExoression of T Ceil Receptor Vg but not Va in Rheumatoid Arthritis. Ettr J fmrrzr~trol 1991,
21:61d6. The polymerase chain reaction was used to estimate the relative fre. quency of different Va and V8 elements in .synovial fluid and peripheml blood lymphocytes of three RA patients. Only a few VP transcripts were used - preferentially V87. but not VP14 - whereas no restriction was seen among the Va elements.
38.
BUCHT A, OKSENBERG J, LINDB~ S, GRONB~RG A, STEiNhlNrl L, KIARESK~C L Characterization of T CelI Receptor Repertoire in Synovial Tissue from Different Temporal Phases of Rheumatoid Arthritis. ScandJ Immunol 1991, in press.
39.
QIN S. WISE M, COBBOID S, LEONG L, KONG Y, PARNES J. WALDMANN H: Induction of Tolerance in Peripheral T Cells with Monoclonal Antibodies. Eztr J fnun~nol 1990,
.
28. .
M~ret~c:~ P. KAPPLER J: The Staphylococcal Their Relatives. Scie~rce I99Q. 248:32%329.
20:2737-2745. Using selected antiCD4 antibodies it was possible to render postthymic T cells of mice tolerant to a range of antigens (human and rat immunoglobulins as well as bone marrow and skin grafts differing from the host at multiple minor histocompatibility antigens). In the cases of human gammaglobulin, tolerance was obtained after antigen was given under the cover of a short course of non-depleting anti-CD4 antibodies. For skin and bone marrow gtafts administration of anti-CD8 antibodies was also required to achieve tolerance.
40.
COBBOLD S, MAR~N G, WAU)~WNN H: The Induction of Skin Graft Tolerance in Major Histocompatibility Complex-Mismatched or Primed Recipients: Primed T Cells can be Tolerized in the Periphery with Anti-CD4 and Anti-CD8 Antibodies. Eur J Immunol 1990, 20~2747-2755. This report shows that tolerance to allogeneic skin grafted at the time of antibody administration can be obtained after administration of blocking anti-CD4 anti-CD8 antibodies in both naive and primed animals. The demonstration of tolerance induction in the case of a primed host has important implications for Further development of human therapy. ..
41.
MA-MESON P, COBBOUI S, HALE G, CLARK M, O~MERA D, LOXWOOD C, WAU)MANN H: Monoclonal Antibody Therapy In Systemic VascuIitls. N Engl J Med 1990, 323:250-254. The humanized antibody Campath-1H and later an anti-CD4 antibody were administered, in the hope that an initial depletion of the bulk of lymphocytes with Campath-lH, and subsequent application of anti-CD4 would induce tolerance to putative autoantigens of pathogenetic impor. tance. A remission was induced that had lasted 12 months when the article was published. .
L Klareskog, of Clinical Sweden.
J RonneUd, Immunology,
S Gudrnundsson, S-751 85 Uppsala
A Karlsson-Parm, Department University Hospital, Uppsala,